title: Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities.
abstract: Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are common in glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The mutant enzymes acquire a neomorphic activity that converts α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D2HG), a rare metabolite. In cells and tissues expressing mutant IDH, D2HG concentrations are highly elevated. D2HG may act as an "oncometabolite" by inhibiting a class of α-KG-dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling. Knock-in mouse models of IDH1 mutations have shed light on these mechanisms and will provide valuable animal models for further investigation.
authors.affiliation: Campbell Family Cancer Research Institute at Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Cairns
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D001120:Arginine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human